New role discovered for protein critical to the development of pancreatic cancer

New role discovered for protein critical to the development of pancreatic cancer

Alec Kimmelman, MD, PhD, recipient of a 2010 Pancreatic Cancer Action Network -- AACR Career Development Award, is a major author on an important publication in the highly prestigious journal Cell. Dr. Kimmelman is an Assistant Professor of Radiation Oncology at Harvard University, and his Pancreatic Cancer Action Network funding is listed among the financial sources of support for this project. Another author on the paper is Aram Hezel, MD, recipient of a 2005 Samuel Stroum – Pancreatic Cancer Action Network -- ASCO Young Investigator Award.

An intriguing finding in this paper is that turning off the expression of mutant K-Ras, a protein known to play a critical role in the development and progression of pancreatic cancer, interferes with the cancer cells’ ability to break down sugar (glucose). Glucose breakdown, called glycolysis, provides a necessary energy source for many cellular activities, including synthesis of new DNA. Although changes in glycolysis have been implicated as a common feature of cancer, it was not previously known that K-Ras activity directly influences glycolysis. This finding helps explain some of the unusual sugar and nutrient breakdown activities of pancreatic cancer cells, and provides new avenues to explore ways to block the disruptive effects of K-Ras mutation.

It has been well established that a mutant form of the protein K-Ras plays a pivotal role in the initiation and progression of pancreatic cancer by stimulating the growth and survival of the cells, generating a strong signal to constantly grow and ignore environmental cues to stop growing. In fact, expression of mutant K-Ras alone into otherwise normal pancreas cells will lead to the development of cancerous characteristics.

In this study, Dr. Kimmelman and colleagues evaluate an elegant mouse model of pancreatic cancer, whereby mutant K-Ras expression facilitates the growth of pancreatic tumors, but then can be genetically manipulated and turned on and off during various stages of the development of the disease. Consistent with previous work (see Pancreatic Cancer Action Network grant recipient Dr. Pasca di Magliano’s recent study here), the authors of this study showed that pancreatic tumor development is dependent on K-Ras expression and activity throughout disease progression.

Since mutant K-Ras activity is so important to pancreatic cancer development, many scientists have aimed to therapeutically block the protein’s expression or activity. Although this can be achieved in a laboratory setting, it has not been possible to target K-Ras in patients. Instead, there has been new research aimed at targeting other proteins that become activated by K-Ras. Based on Dr. Kimmelman and colleagues’ findings reported in this paper, attacking proteins involved in the sugar breakdown process may be attractive targets to stop the growth of pancreatic cancer cells. Additional studies in the laboratory will be necessary before this strategy could potentially be translated for clinical benefit.

The Pancreatic Cancer Action Network encourages all patients to consider clinical trials when exploring treatment options. For more information about ongoing clinical trials or any other questions about pancreatic cancer treatment or diagnosis, please contact a Pancreatic Cancer Action Network Patient and Liaison Services (PALS) Associate toll-free at 877-272-6226 or email pals@pancan.org. PALS Associates are available M-F 7am-5pm Pacific Time.

Click here to see the Dana-Farber Cancer Institute press release about this paper.
Click here for the paper’s scientific abstract.

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